Ethanamine, 2,2,2-trifluoro- → tert-Butyl (2R,5S)-2-[2-(3-{[N-(tert-butoxycarbonyl)-4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]amino}-5-fluoropyridin-4-yl)ethyl]-5-({[(2,2,2-trifluoroethyl)carbamoyl]oxy}methyl)morpholine-4-carboxylate

HRID 629738Notes

Reaction equation

HRID 629738 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([F:51])[C:33]=1[CH2:34][CH2:35][C@H:36]1[O:41][CH2:40][C@@H:39]([CH2:42][OH:43])[N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:37]1)=[O:26])[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:57](N2C=NC=C2)=[O:58])C=1.[F:64][C:65]([F:69])([F:68])[CH2:66][NH2:67]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([F:51])[C:33]=1[CH2:34][CH2:35][C@H:36]1[O:41][CH2:40][C@@H:39]([CH2:42][O:43][C:57](=[O:58])[NH:67][CH2:66][C:65]([F:69])([F:68])[F:64])[N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:37]1)=[O:26])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

5

Reactant 3

HCID 9773Ethanamine, 2,2,2-trifluoro-2×HCID 682631,1'-CarbonyldiimidazoleHCID 86726337HCID 86726337, compound

Product 1

HCID 86726338tert-Butyl (2R,5S)-2-[2-(3-{[N-(tert-butoxycarbonyl)-4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]amino}-5-fluoropyridin-4-yl)ethyl]-5-({[(2,2,2-trifluoroethyl)carbamoyl]oxy}methyl)morpholine-4-carboxylateYield 73.3%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
60 °C

Procedure

tert-Butyl (2R,5R)-2-[2-(3-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-5-fluoropyridin-4-yl)ethyl]-5-(hydroxymethyl)morpholine-4-carboxylate (1.50 g, 2.10 mmol) and CDI (0.425 g, 2.62 mmol) were heated at 60° C. in Pyridine (21 mL) for 30 min. 2,2,2-Trifluoroethylamine (3.29 mL, 42.0 mmol) was added and the reaction heated at 60° C. for 24 hours, A further aliquot of 2,2,2-Trifluoroethylamine (1.65 mL, 21.0 mmol) was added and the reaction heated at 60° C. for a further 24 hours. The reaction was quenched with saturated aqueous KH2PO4 then brine and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (220 g) eluting with a gradient of 0-100% EtOAc/hexanes afforded the title compound (1.29 g, 1.54 mmol, 73% yield) as a white solid, MS (ESI): m/z=840.46 (MH+); 100% pure by LCMS.

Workup

  1. temperaturethe reaction heated at 60° C. for a further 24 hours
  2. customThe reaction was quenched with saturated aqueous KH2PO4
  3. extractionbrine and the mixture was extracted with ethyl acetate (×3)
  4. dry with materialThe combined organic fractions were dried (MgSO4)
  5. filtrationfiltered
  6. customthe solvent was evaporated under reduced pressure
  7. customPurification on silica gel (220 g)
  8. washeluting with a gradient of 0-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-fd5c542b423544608d625567ad25798a
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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